Novel amino estratetraenes, intermediates, and process



United States Patent Ofifice 3,055,885 Patented Sept. 25, 1962 Theinvention relates to novel 3-amino-17/3-acyloxy- A -estratetraencshaving the formula:

wherein Ac is an acyl radical of an organic carboxylic acid having 1 to18 carbon atoms and R and R are selected from the group consisting ofhydrogen, lower alkyl and lower hydroxy alkyl and when taken togetherform a heterocyclic ring selected from the group consisting ofpyrrolidyl, piperidyl and morpholino. The inven tion further relates tonovel processes for producing said amino estratetraenes andintermediates thereof.

This application is a continuation-in-part of Serial No. 59,166, filedSeptember 29, 1960, and Serial No. 110,329, filed May 16, 1961, bothabandoned.

As intermediates, more particularly, it relates to novel 811,90: epoxy35 methyl 7 oxo 8B (3 oxobutyl) 3,4 [3'19 acyloxy cylopentano (2,l')]decahydronaphthalene compounds of the formula:

It is a further object of the invention to provide novel 6 intermediatesfor the preparation of compounds of Formula I.

Another object of this invention is the production of 811,911 epoxy 318methyl 7 oxo 8B (3' oxobutyl)- 2 3,4-[3'fl-acyloxy-cyclopentanm(2',1')]decahydronaphthalene compounds of the structural formula:

wherein Ac represents the acyl radical of an organic carboxylic acidhaving from 1 to 18 carbon atoms, and especially8a,9-epoxy-3B-mcthyl-7-oxo-8B-(3'-oxobutyl)- 3,4-[3'p-benzoyloxycyclopentano-(2',1')] decahydronaphthalene.

These and other objects and advantages of the invention will becomeobvious from the following detailed descrlption.

The B-amino-estratetraenes of the invention have the formula:

wherein Ac is the acyl radical of an organic carboxylic acid having 1 to18 carbon atoms and R and R; are selected from the group consisting ofhydrogen, lower alkyl and lower hydroxy alkyl and when taken togetherform a heterocyclic ring selected from the group consisting ofpyrrolidyl, piperidyl and morpholino.

The organic carboxylic acid having 1 to '18 carbon atoms may bealiphatic, cycloalkyl or aromatic. Suitable organic carboxylic acids arealkanoic and alkenoic such as acetic acid, trimethylacetic acid,propionic acid, butyric acid, 4,4-dimethylpentanoic acid, IO-undecenoicacid; cycloalkyl alkanoic acids such as B-cyclopentyl propionic acid;arylalkanoic acids such as phenyl propionic acid, phenoxyacetic acid;cycloalkanoic acids such as hexahydrobenzoic acid, hexahydroterephthalicacid; and phenyl carboxylic acids such as benzoic acid and 3,5-dinitrobenzoic acid.

The process for the preparation of the compounds of Formula H consistsessentially of subjecting M -313- methyl-7-oxo-8-(3'-oxobutyl)-3,4-[3p-acyloxy cyclopentano-(2',1')]-octahydronaphthalenecompounds having the structural formula 0 wherein Ac has the meaningindicated above, in an inert organic solvent to a reaction withoxidizing agents capable of replacing the double bond in the 8,9position by an oxide bridge, such as particularly the organic per- 3carboxylic acids. It is particularly advantageous to use, as thepercarboxylic acid, perphthalic acid.

The starting compounds are obtained according to the where Ac has themeaning given above, to a condensation reaction with1,3-dichloro-2-butene in the presence of an alkaline condensation agentand hydrolyzing the resulting A-3fl-methyl-7-oxo-8-(3'-chloro-2'-butenyl)- 3,4-[3'p-acyloxycyclopentano-(2',l')J-octahydronaphthalene compounds of the formula:

wherein Ac has the above definition with an acid salt of a primary orsecondary amine to form the 3-amino-17flacyloxy-A -estratetraene ofFormula I and recovering said estratetraene.

The amine reactant has the formula:

' R1 wherein R and R have the above definition. Examples of suitableamines for the action are ammonia, methylamine, ethylamine, monoethanolamine, dimethyl amine, diethylamine, pyrrolidine, piperidine,morpholine, etc. The acid salt is preferably the acetate salt.

The reaction is preferably efl ected by mixing the reactants in anon-polar organic solvent such as benzene or toluene and heating thesolution to the reflux temperature of the solvent until the reaction iscomplete, usually one-half hour to one hour. After washing the reactionmixture with water and evaporating olf the solvent, a residue isobtained and may be purified by crystallization from organic solventssuch as methanol, ether, etc.

The second process for the preparation of the compounds of 'Formula Icomprises cyclizing a 8a,9m-epoxy-3p-methyl-7-oxo-8fl-(3'-oxobutyl)-3,4-[3'p-acyloxycyclopentano-(2,1)]-decahydronaphthalene of Formula H under alkalineconditions to form the corresponding ester of911,1Oa-epoXy-I9-nor-testosterone, reacting the latter with a primary orsecondary amine having the formula:

4 wherein R and R have the above definitions to form a 3-amino-Qa-hydroxy-17B-acyloxy-A -estratriene having the formula:

III

wherein R, R and Ac have the above definitions, dehydrating the latterto form compounds of Formula I and recovering the product.

A preferred process for the preparation of compounds of Formula '1comprises cyclizing the8a,9a-epOXy-3fimethyl-7-oxo-8fl-(3'-oxobutyl)-3,4-[3'p-acy1oxycyclopentano (2,1')J-decahydronaphthalene with an alkali metal acetatesuch as sodium acetate or potassium acetate in the presence of ahydroxide of the same metal in a solvent such as dioxane to form thecorresponding ester of 9a,'10a-epoxy-19-nor-testosterone, reacting thesaid ester with a primary or secondary amine in a lower a1- kanol suchas methanol in the presence of a mutual solvent such as benzene ortoluene to form the corresponding 3-amino-9u-hydroxy-17B-acyloxy-Aestratriene, dehydrating the latter dissolved in an inert solvent suchas benzene with acetic acid to form the compound of Formula I andrecovering said compound. The reaction scheme is illustrated in Table I.

TABLE I Example I PREPARATION OF 8a,9a-EPOXY-3B-METHYLr7-OXO-8B- (3'OXOBUTYL) 3,4 [3's BENZOYLOXY CYCLO- PENTANO (2',1')]DECAHYDRONAPHTHALENE, II, Ae=CeHsCO 0.100 gm. of A-3fi-methyl-7-oxo-8-(3'-oxobutyl)-3,4-[3,6-benzoyloxy-cyclopentano-(2',1)] octahydronaphthalene was dissolvedin 1 cc. of dry dichlor-ethane, then 0.30 cc. of a 25% ethereal solutionof perphthalic acid was added thereto under agitation and in anatmosphere of nitrogen. The reaction mixture was agitated overnight atroom temperature, next, the phthalic acid formed was vacuum filtered andthe filtrate solution was washed succesively with a 1% sodium bisulfatesolution, with water, with sodium bicarbonate and again with water. Thewashed solution was dried over sodium sulfate and evaporated to drynessin vacuo to recover a colorless resin,8a,9u-epoxy-3p-rnethyl-7-oxo-8fl-(3-oxo-butyl)3,4-[3flbenzoyloxy-cyclopentano '(2',1')] decahydronaphthalene, II, Ac=CH CO, 'which was purified by dissolving in hot isopropyl ether andcrystallizing by icing. The yield was 0.061 gm. (that is, 60% of theory)of the product which was obtained in the form of colorless prismaticcrystals having a melting point of 147 C. This product was soluble inmost of the customary organic solvents such as ether, acetone, benzene,chloroform, methyl and ethyl alcohol etc., and insoluble in water anddilute aqueous acids or alkalies.

Analysis:--C H O molecular weight=410.49. Calculated: C, 73.14%; H,7.37%. Found: C, 72.9%; H, 7.5%.

The infra-red spectrum shows the presence of three bands which arecharacteristic of the epoxide function at 929 cmr 833 cm. and 810 cm.

This product is not described in the literature.

The starting material is obtained by condensation of A-3fi-methyl-7-oxo-3,4-[3'5 benzoyloxycyclopentano-(2,1)]-octahydronaphthalene with 1,3-dichloro-2- butene inthe presence of sodium ter-amylate and hydrolysis of the resulting A-3fl-methyl-7-oxo-8-(3'-chloro-2'-butenyl)-3,4-[3'fl-benzoyloxy-cyclopentano (2',1)]-octahydronaphthalene,as it has been described in U.S. Patent 3,019,252.

Example II PREPARATION OF 3-PYRROLIDYL-17B-BENZOYLOXY- A 0J-ESTRATETRAENE 0.040 g. of8a,9u-epoxy-3B-methyl-7-oxo-8B-(3'-oxobutyl)-3,4-[3'fi-benzoyloxy-cyclopentano-(2',1')]decahydronaphthalene, melting at 147 C., obtained according to Example Iwere dissolved under a nitrogen atmosphere in 1.6 cc. of anhydrousbenzene. 0.25 cc. of pyrrolidine were added to the solution. Thesolution was neutralized by 0.25 cc. of acetic acid, agitated and thereaction mixture allowed to stand in an atmosphere of nitrogen for aperiod of several minutes. A golden yellow color appeared. The reactionmixture was heated to reflux for a period of an hour, then aftercooling, washed with water and dried over magnesium sulfate. The benzenesolution was distilled to dryness under vacuum and the residue aftertrituration in isopropyl ether consisted of 0.035 g. of crystals of3-pyrrolidyl-17B -benzoyloxy- A -estratetraene which was purified byrecrystallization in methanol. The yield was 0.030 g. of product meltingat 240 C.

Ultra-violet spectrum (in ether after dissolution in methylenechloride):

Ultra-violet spectrum '(in a mixture of ether-ethanol and 10 Nhydrochloric acid):

The product was present in the form of fine pale yellow needles, verysoluble in benzene, soluble in chloroform, isopropyl ether, slightlysoluble .in methanol or ethanol, and insoluble in water and diluteaqueous alkalies.

The product has not been described in the literature.

Example III PREPARATION OF 3-'(B-HYDROXYETHYL)-AMINO-17fl- BENZOYLOXY-A-ESTRATETRAENE 30 mg. of 8a,9a-epoxy 3 3methyl-7-oxo-8fl-(3'-oxobutyl)3,4-[3',8-benzoyloxy-cyclopentano-(2,1)]decahydronaphthalene, melting point 147 C., were introduced into 2 cc.of anhydrous toluene and 0.25 cc. of ethanolamine was added. Thereaction mixture was neutralized by 0.25 cc. of acetic acid and heatedto reflux under agitation in an atmosphere of nitrogen for a half hour.The reaction mixture was then cooled and the toluene solution washedwith water. It was evaporated to dryness under vacuum and a residue wasobtained comprising 3- ,S-hydroxyethyD-amino-17,8-benzoyloxy Aestratetraene which was crystallized from isopropyl ether andrecrystallized in methanol. The product was present in the form ofbrilliant needles melting at 182-183 C.

Ultra-violet spectrum (ethanol):

rm, 228 mp, E12"... 590 m. 284 m EH1... 550 (Ethanol N/ hydrochloricacid):

am. 221 mu, E12,, 543 Am... 229 my, Etta... 564 Am. 260 m Elfi 400Inflexion about 266, 290 and 300 m This product is not described in theliterature.

Example IV PREPARATION OF 3-PYRROLIDYL-17fi-BENZOYLOXY- A -ESTRATETRAENEStep A.-0.250 g. of racemic 8a,9a-epoxy-3fi-methyl-7-oxo-8B-(3-oxobutyl)-3,4-[3fl-benzoyloxy cyclopentano-(2,1)]-decahydronaphthalene melting at 147 C. were introduced into 20cc. of pure dioxane. The starting material was obtained according toExample I. The reaction mixture was agitated in an atmosphere ofnitrogen for a period of several minutes and 0.800 g. of potassiumacetate and 1.15 cc. of distilled water were added. After the reactionmixture was agitated for a period of five minutes at room temperature,0.40 cc. of a 50% potassium hydroxide solution were introduced and theagitation was continued at room temperature and under an atmosphere ofnitrogen for a period of 15 hours. 10 cc. of water and 50 cc. of etherwere then added. The aqueous phase was decanted and the etherealextracts were evaporated under vacuum. A residue of 0.240 g. wasobtained which was redissolved in methylene chloride and subjected tochromatography through silicagel. On elution with methylene chloridecontaining 2% acetone, 0.150 g. of the racemic benzoate of9a,10a-epoxy-19-nortestosterone was recovered which afterrecrystallization from methanol had a melting point of 167 C.

The product occurred in the form of colorless prismatic crystals, verysoluble in benzene, soluble in ether, and methanol, and insoluble inwater and dilute aqueous acids or alkalies.

This product is not described in the literature.

By application of the above described process to the dextrorotatoryenantiomorph of 8a,9a-epoxy 3 fl-methyl-7-oxo-8fi-(3'-oxobutyl)-3,4-[3'fi-benzoyloxy cyclopentano-(2.,1)J-decahydronaphthalene, melting at 140 C. and having a specificrotation [a] =-|133 (c.=1%, chloroform), the corresponding tetracyclicepoxide was obtained having a melting point of 173 C. and having aspecific rotation [a] =+112 (c.=1%, methanol).

This product is not described in the literature.

Step B.--0.l g. of the racemic benzoate of9a,l0aepoxy-l9-nor-testosterone was dissolved in 1 cc. of anhydrousbenzene. 3 cc. of a methanolic solution containing 3.3% of pyrrolidinewere added under an atmosphere of nitrogen and the reaction mixture wasagitated at room temperature for a period of one hour. The solution hada yellow color after several minutes of agitation. At the end of thereaction the solvent was evacuated under vacuum and the residuetriturated with isopropyl ether. After vacuum filtration, the productwas washed with isopropyl ether, dried, and 0.080 g. of a productconstituting the 17-benzoate of 3-pyrrolidyl-9a,17li-dihydroxy- A-estratriene, melting at 200 C. was recovered. The compound, which waspresent in the form of white platelets, was soluble in benzene,chloroform, and a 1:1 mixture of benzene and methanol, slightly solublein ether, and insoluble in water and dilute aqueous alkalies.

AnaIysis.-C H O N; molecular weight=445 .6. Calculated: C, 78.17%; H,7.92; N, 3.15%. Found: C, 78.6%; H, 7.8%; N, 3.3%.

Ultra-violet spectrum in methylene chloride-ether mixture:

This product is not described in the literature.

Step C.0.070 g. of the l7-benzoate of S-pyrrolidyl- 9m,l7fi-dihydroxy-A-estratriene, melting at 200 C., were introduced into 5 cc. of benzene.0.5 cc. of acetic acid were added and the reaction mixture was heated toreflux. After heating for a period of two hours, the reaction mixturewas cooled, a solution of sodium bicarbonate added, and the reactionmixture extracted with chloroform. The extracts were combined and aftervacuum evaporation of the extracts to dryness a residue was obtainedcomprising 3-pyrrolidyl 17,3 benzoyloxy-A estr-atetraene which wasrecrystallized in methanol, melting point 240 C.

This product is identical to that described in Example II.

Various modifications of the process and/or products of the presentinvention may be made without departing from the spirit or scopethereof, and it is to be understood that the invention be limited onlyas defined in the appended claims. We claim: 1. A compound having theformula:

one

wherein Ac is the acyl radical of an organic carboxylic acid having 1 to18 carbon atoms and R and R are selected from the group consisting ofhydrogen, lower alkyl, and lower hydroxyalkyl and when taken togetherform a heterocyclic ring selected from the group consisting ofpyrrolidyl, piperidyl and morpholino.

8 2. 3 pyrrolidyl 17B benzoyloxy A -estratetraene.

3. 3 (/8 hydroxyethyl) amino 17,8 benzoyloxy- A -estratetraene.

4. A compound having the formula:

wherein Ac is the acyl radical of an organic carboxylic acid having 1 to18 carbon atoms.

7. The benzoate ester of 9a,l0u-epoxy-19-nor-testosterone.

8. 8a,9a-epoxy-3fi-methyl-7-oxo-8p-(3'-oxobutyl) 3,4-[3'fl-acyloxy-cyclopentano-(2, 1) ]-decahydronaphthalene compounds ofthe structural formula:

wherein Ac is the acyl radical of an organic carboxylic acid having 1 to18 carbon atoms.

10. A process for the preparation of compounds having the formula:

OAc

wherein Ac is the acyl radical of an organic carboxylic acid having 1 to18 carbon atoms and R and R are selected from the group consisting ofhydrogen, lower alkyl, and lower hydroxyalkyl and when taken togetherform a heterocyclic ring selected from the group consisting ofpyrrolidyl, piperidyl and morpholino, which comprises reacting acompound having the formula:

wherein Ac has the above definition with the acid salt of an aminehaving the formula:

wherein R and R have the above definitions and recovering the desiredproduct.

11. The process of claim 10, wherein 8a,9a-epoxy-3B- methyl-7-oxo-8fi-(3 '-oxobuty1) 3,4- 3 'flbenzoyloxy-cyclopentano-(2',1)l-decahydronaphthalene is reacted with theacid salt of the said amine.

12. The process of claim 10, wherein the acid salt of the amine is theacetate salt of pyrrolidine.

13. The process of claim 10, wherein the acid salt of the amine is theacetate salt of ethanolamine.

14. The process of claim 10, wherein the reaction is conducted in anon-polar solvent at its reflux temperature.

15. A process for the preparation of a compound having the formula:

wherein Ac is the acyl radical of an organic carboxylic acid having 1 to18 carbon atoms and R and R are selected from the group consisting ofhydrogen, lower alkyl, and lower hydroxyalkyl and when taken togetherform a heterocyclic ring selected from the group consisting ofpyrrolidyl, piperidyl and morpholino which comprises cyclizing acompound having the formula:

wherein Ac has the above definition to form the corresponding ester of9a,10a-epoxy-19-nor-testosterone with an alkali metal acetate in thepresence of a hydroxide of the same alkali metal, reacting the latterwith an amine having the formula:

wherein R and R have the above definitions to form compound having theformula:

10 wherein R, R and Ac have the above definitions, dehydrating thelatter with acetic acid at reflux temperatures to form the desiredcompound and recovering said compound.

16. The process of claim 15, wherein the cyclization is effected withpotassium acetate in the presence of potassium hydroxide.

17. The process of claim 15, wherein the cyclization is effected insolution in dioxane.

18. The process of claim 15, wherein 8a,9a-epoxy-3fimethyl-7-oxo-8 8-3-oxobutyl) -3,4- E3'fi-benzoyloxy-eyclopentano-(2',1')]-decahydronaphthalene is thecompound cyclized.

19. The process of claim 15, wherein the amine is pyrrolidine.

20. The process of claim 15, wherein the reaction with the amine iseflected in a mixture of methanol and benzene.

21. A process for the production of 3-pyrrolidyl-17pbenzoyloxy-A-estratetraene which comprises the steps of reacting A -33-methyl-7-oxo-8-(3'-oxobutyl) -3 ,4- 3'fi-benzoyloxy-cyclopentano-(2, 1) ]-octahydronaphthalene in an inertorganic solvent with perphthalic acid, cyclizing the8a,9u-epoxy-3fi-methyl-7-oxo-8B-(3'- oxobutyl)3,4-[3'flbenzoyloxy-cyclopentano (2,1')]- decahydronaphthalene with potassiumacetate in the presence of potassium hydroxide in dioxane to form thebenzoateester of 9a,10a-epoxy-19-nor-testosterone, reacting the latterwith pyrrolidine in a solvent mixture of benzene and methanol to form3-pyrrolidyl-9u-hydroxy- 17p-benzoyl0xy-A -estratriene, dehydrating thelatter with acetic acid to form 3-pyrrolidyl-l7fl-benzoyloxy- A-estratetraene and recovering said product.

22. A process for the production of 3-pyrrolidyl-17fibenzoyloxy-A-estratetraene vwhich comprises the steps of reacting A-3}8-methy1-7-oxo-8-(3-oxobutyl)-3a,4fi-[3'B-benzoyloxy-cyclopentano-(2',1') -octahydronaphthalene in an inertorganic solvent with perphthalic acid, reacting the811,9u-epoxy-3fl-methyl-7-oxo- 8fl-(3'-oxobutyl(-3,4-[3'B-benzoyloxycyclopentano (2', 1')]-decahydronaphthalene with pyrrolidine in thepresence of a lower alkanoic acid and an inert organic solvent at refluxtemperature and recovering said estratetraene.

23. The process of producing 8a,9a-epoxy-3fi-methyl-7-oxo-8B-(3-oxobutyl)-3,4-[3'fi-benzoyloxy cyclopentano-(2.,1')l-decahydronaphthalene, which comprises the steps of reacting A-3fi-methyl-7-oxo-8-(3-oxobutyl)-3,4- [3'fi-benzoyloxy-cyclopentano-(2',1 l-octahydronaphthalene in an inert organic solvent with perphthalicacid, and recovering said 8,9-epoxy naphthalene.

References Cited in the file of this patent UNITED STATES PATENTS2,673,847 Spero et a1. Mar. 30, 1954 2,793,233 Stork May 21, 19572,838,492 Pederson et a1. June 10, 1958

1. A COMPOUND HAVING THE FORMULA: